The purpose of the proposed studies is to develop methods which allow successful clinical transplantation of pancreatic and parathyroid tissue without the need for immunosuppressive therapy. The studies proposed in the first part of this grant are aimed at the further clarification of the mechanism of induction of alloimmunity by passenger cells. We are planning to use the thyroid transplant model and congenic mouse strains in combination with genetically defined mice serving as interim hosts. We will test our hypothesis suggesting that antigen and co-stimulator have to be presented by one cell in order to stimulate a maximal response to major histocompatibility antigens. In the second part of the proposed study, we are planning to transplant fetal pancreatic tissue into diabetic mice. The interim host system will be used to deplete fetal mouse pancreatic tissue from its passenger cell contents. Culture in high oxygen atmosphere will be combined with immunotoxin treatment of the interim host. In addition, fluorocarbon will be used to inactivate passenger cells residing in fetal pancreatic tissue. The novelty of the proposed approach is the simultaneous use of interim hosting and passenger leukocyte depleting treatment modalities. In further experiments, human fetal pancreatic tissue will be treated in a similar manner and monitoring of its passenger leukocyte contents will be performed by the use of immunofluorescence and immunoperoxidase techniques. If we should be successful in preserving the metabolic integrity of human fetal pancreatic tissue and at the same time are able to deplete this tissue from passenger cells, we will proceed with the transplantation of this tissue into patients with juvenile onset diabetes. In the initial phase of these studies, human fetal pancreatic tissue will be placed beneath the kidney capsule of patients simultaneously receiving a kidney transplant. Our long-term goal is to transplant human fetal pancreatic tissue to non-immunosuppressed patients. The second clincal study is an extension of the previously described clinical parathyroid transplantation. Human parathyroid tissue pretreated and interim hosted will be transplanted to patients with iatrogenic and congenital hypoparathyroidism.